Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the elderly that is characterized by memory loss. Neuropathologically, the AD brain is marked by an increased Aβ burden, hyperphosphorylated tau aggregates, synaptic loss, and inflammatory responses. Disturbances in calcium homeostasis are also one of the earliest molecular changes that occur in AD patients, alongside alterations in calcium-dependent enzymes in the post-mortem brain. The sum of these studies suggests that calcium dyshomeostasis is an integral part of the pathology, either influencing Aβ production, mediating its effects or both. Increasing evidence from in vitro studies demonstrates that the Aβ peptide could modulate a number of ion channels increasing calcium influx, including voltage-gated calcium and potassium channels, the NMDA receptor, the nicotinic receptor, as well as forming its own calcium-conducting pores. In vivo evidence has shown that Aβ impairs both LTP and cognition, whereas all of these ion channels cluster at the synapse and underlie synaptic transmission and hence cognition. Here we consider the evidence that Aβ causes cognitive deficits through altering calcium homeostasis at the synapse, thus impairing synaptic transmission and LTP. Furthermore, this disruption appears to occur without overt or extensive neuronal loss, as it is observed in transgenic mouse models of AD, but may contribute to the synaptic loss, which is an early event that correlates best with cognitive decline
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References
Arispe, N., Rojas, E., and Pollard, H. B. (1993). Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci U S A 90, 567–571.
Bennett, B. D., Denis, P., Haniu, M., Teplow, D. B., Kahn, S., Louis, J. C., Citron, M., and Vassar, R. (2000). A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer’s beta-secretase. J Biol Chem 275, 37712–37717.
Benzing, W. C., Wujek, J. R., Ward, E. K., Shaffer, D., Ashe, K. H., Younkin, S. G., and Brunden, K. R. (1999). Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging 20, 581–589.
Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., and LaFerla, F. M. (2005). Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45, 675–688.
Bliss, T. V., and Collingridge, G. L. (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 31–39.
Bobich, J. A., Zheng, Q., and Campbell, A. (2004). Incubation of nerve endings with a physiological concentration of Abeta1–42 activates CaV2.2(N-Type)-voltage operated calcium channels and acutely increases glutamate and noradrenaline release. J Alzheimers Dis 6, 243–255.
Brown, S. T., Scragg, J. L., Boyle, J. P., Hudasek, K., Peers, C., and Fearon, I. M. (2005). Hypoxic augmentation of Ca2+ channel currents requires a functional electron transport chain. J Biol Chem 280, 21706–21712.
Caccamo, A., Oddo, S., Billings, L. M., Green, K. N., Martinez-Coria, H., Fisher, A., and LaFerla, F. M. (2006). M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49, 671–682.
Chapman, P. F., White, G. L., Jones, M. W., Cooper-Blacketer, D., Marshall, V. J., Irizarry, M., Younkin, L., Good, M. A., Bliss, T. V., Hyman, B. T., et al. (1999). Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci 2, 271–276.
Chen, M., and Fernandez, H. L. (2004). Stimulation of beta-amyloid precursor protein alpha-processing by phorbol ester involves calcium and calpain activation. Biochem Biophys Res Commun 316, 332–340.
Chen, Q. S., Kagan, B. L., Hirakura, Y., and Xie, C. W. (2000). Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides. J Neurosci Res 60, 65–72.
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., and Holtzman, D. M. (2005). Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913–922.
Colvin, R. A., Bennett, J. W., Colvin, S. L., Allen, R. A., Martinez, J., and Miner, G. D. (1991). Na+/Ca2+ exchange activity is increased in Alzheimer’s disease brain tissues. Brain Res 543, 139–147.
Coon, A. L., Wallace, D. R., Mactutus, C. F., and Booze, R. M. (1999). L-type calcium channels in the hippocampus and cerebellum of Alzheimer’s disease brain tissue. Neurobiol Aging 20, 597–603.
Cruz, J. C., Tseng, H. C., Goldman, J. A., Shih, H., and Tsai, L. H. (2003). Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40, 471–483.
DeKosky, S. T., Scheff, S. W., and Styren, S. D. (1996). Structural correlates of cognition in dementia: quantification and assessment of synapse change. Neurodegeneration 5, 417–421.
Demuro, A., Mina, E., Kayed, R., Milton, S. C., Parker, I., and Glabe, C. G. (2005). Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280, 17294–17300.
Ekinci, F. J., Malik, K. U., and Shea, T. B. (1999). Activation of the L voltage-sensitive calcium channel by mitogen-activated protein (MAP) kinase following exposure of neuronal cells to beta-amyloid. MAP kinase mediates beta-amyloid-induced neurodegeneration. J Biol Chem 274, 30322–30327.
Fahrenholz, F., and Postina, R. (2006). Alpha-secretase activation–an approach to Alzheimer’s disease therapy. Neurodegener Dis 3, 255–261.
Garlind, A., Cowburn, R. F., Forsell, C., Ravid, R., Winblad, B., and Fowler, C. J. (1995). Diminished [3H]inositol(1,4,5)P3 but not [3H]inositol(1,3,4,5)P4 binding in Alzheimer’s disease brain. Brain Res 681, 160–166.
Gibson, G. E., Nielsen, P., Sherman, K. A., and Blass, J. P. (1987). Diminished mitogen-induced calcium uptake by lymphocytes from Alzheimer patients. Biol Psychiatry 22, 1079–1086.
Goto, Y., Niidome, T., Akaike, A., Kihara, T., and Sugimoto, H. (2006). Amyloid beta-peptide preconditioning reduces glutamate-induced neurotoxicity by promoting endocytosis of NMDA receptor. Biochem Biophys Res Commun 351, 259–265.
Green, K. N., and Peers, C. (2001). Amyloid beta peptides mediate hypoxic augmentation of Ca(2+) channels. J Neurochem 77, 953–956.
Green, K. N., and Peers, C. (2002). Divergent pathways account for two distinct effects of amyloid beta peptides on exocytosis and Ca(2+) currents: involvement of ROS and NF-kappaB. J Neurochem 81, 1043–1051.
Greenamyre, J. T., Penney, J. B., D’Amato, C. J., and Young, A. B. (1987). Dementia of the Alzheimer’s type: changes in hippocampal L-[3H]glutamate binding. J Neurochem 48, 543–551.
Grynspan, F., Griffin, W. R., Cataldo, A., Katayama, S., and Nixon, R. A. (1997). Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer’s disease. Brain Res 763, 145–158.
Hedin, H. L., Eriksson, S., and Fowler, C. J. (2001). Human platelet calcium mobilisation in response to beta-amyloid (25–35): buffer dependency and unchanged response in Alzheimer’s disease. Neurochem Int 38, 1450–151.
Hirashima, N., Etcheberrigaray, R., Bergamaschi, S., Racchi, M., Battaini, F., Binetti, G., Govoni, S., and Alkon, D. L. (1996). Calcium responses in human fibroblasts: a diagnostic molecular profile for Alzheimer’s disease. Neurobiol Aging 17, 549–555.
Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., et al. (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nat Med 4, 97–100.
Huang, H. M., Toral-Barza, L., Thaler, H., Tofel-Grehl, B., and Gibson, G. E. (1991). Inositol phosphates and intracellular calcium after bradykinin stimulation in fibroblasts from young, normal aged and Alzheimer donors. Neurobiol Aging 12, 469–473.
Ibarreta, D., Parrilla, R., and Ayuso, M. S. (1997). Altered Ca2+ homeostasis in lymphoblasts from patients with late-onset Alzheimer disease. Alzheimer Dis Assoc Disord 11, 220–227.
Kawahara, M., and Kuroda, Y. (1997). [Molecular mechanism of neuronal death in Alzheimer’s disease: Ca(2+)-channel formation of beta amyloid protein molecules]. Tanpakushitsu Kakusan Koso 42, 2002–2010.
Kishimoto, A., Mikawa, K., Hashimoto, K., Yasuda, I., Tanaka, S., Tominaga, M., Kuroda, T., and Nishizuka, Y. (1989). Limited proteolysis of protein kinase C subspecies by calcium-dependent neutral protease (calpain). J Biol Chem 264, 4088–4092.
LaFerla, F. M. (2002). Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci 3, 862–872.
Lee, M. S., and Tsai, L. H. (2001). Cdk5 at the junction. Nat Neurosci 4, 340–342.
Leissring, M. A., Akbari, Y., Fanger, C. M., Cahalan, M. D., Mattson, M. P., and LaFerla, F. M. (2000). Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 149, 793–798.
Lim, G. P., Chu, T., Yang, F., Beech, W., Frautschy, S. A., and Cole, G. M. (2001). The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21, 8370–8377.
Liu, F., Grundke-Iqbal, I., Iqbal, K., Oda, Y., Tomizawa, K., and Gong, C. X. (2005). Truncation and activation of calcineurin A by calpain I in Alzheimer disease brain. J Biol Chem 280, 37755–37762.
Liu, Q., Kawai, H., and Berg, D. K. (2001). beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci U S A 98, 4734–4739.
Liu, Y., Peterson, D. A., and Schubert, D. (1998). Amyloid beta peptide alters intracellular vesicle trafficking and cholesterol homeostasis. Proc Natl Acad Sci U S A 95, 13266–13271.
Liu, Y., and Schubert, D. (1997). Cytotoxic amyloid peptides inhibit cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction by enhancing MTT formazan exocytosis. J Neurochem 69, 2285–2293.
Morris, R. G., and erson, E., Lynch, G. S., and Baudry, M. (1986). Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319, 774–776.
Nabeshima, T., and Nitta, A. (1994). Memory impairment and neuronal dysfunction induced by beta-amyloid protein in rats. Tohoku J Exp Med 174, 241–249.
Nomura, I., Kato, N., Kita, T., and Takechi, H. (2005). Mechanism of impairment of long-term potentiation by amyloid beta is independent of NMDA receptors or voltage-dependent calcium channels in hippocampal CA1 pyramidal neurons. Neurosci Lett 391, 1–6.
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H., and LaFerla, F. M. (2004). Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332.
Oddo, S., Caccamo, A., Kitazawa, M., Tseng, B. P., and LaFerla, F. M. (2003a). Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging 24, 1063–1070.
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., and LaFerla, F. M. (2003b). Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39, 409–421.
Oddo, S., Caccamo, A., Tran, L., Lambert, M. P., Glabe, C. G., Klein, W. L., and LaFerla, F. M. (2006). Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281, 1599–1604.
Palotas, A., Kalman, J., Laskay, G., Juhasz, A., Janka, Z., and Penke, B. (2001). Comparative studies on [Ca2+]i-level of fibroblasts from Alzheimer patients and control individuals. Neurochem Res 26, 817–820.
Peskind, E. R., Potkin, S. G., Pomara, N., Ott, B. R., Graham, S. M., Olin, J. T., and McDonald, S. (2006). Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 14, 704–715.
Peterson, C., Gibson, G. E., and Blass, J. P. (1985). Altered calcium uptake in cultured skin fibroblasts from patients with Alzheimer’s disease. N Engl J Med 312, 1063–1065.
Peterson, C., and Goldman, J. E. (1986). Alterations in calcium content and biochemical processes in cultured skin fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci U S A 83, 2758–2762.
Peterson, C., Ratan, R. R., Shelanski, M. L., and Goldman, J. E. (1986). Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors. Proc Natl Acad Sci U S A 83, 7999–8001.
Peterson, C., Ratan, R. R., Shelanski, M. L., and Goldman, J. E. (1988). Altered response of fibroblasts from aged and Alzheimer donors to drugs that elevate cytosolic free calcium. Neurobiol Aging 9, 261–266.
Petryniak, M. A., Wurtman, R. J., and Slack, B. E. (1996). Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism. Biochem J 320 ( Pt 3), 957–963.
Pettit, D. L., Shao, Z., and Yakel, J. L. (2001). beta-Amyloid(1–42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci 21, RC120.
Pierrot, N., Ghisdal, P., Caumont, A. S., and Octave, J. N. (2004). Intraneuronal amyloid-beta1–42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. J Neurochem 88, 1140–1150.
Pontremoli, S., Melloni, E., Michetti, M., Sparatore, B., Salamino, F., Sacco, O., and Horecker, B. L. (1987). Phosphorylation by protein kinase C of a 20-kDa cytoskeletal polypeptide enhances its susceptibility to digestion by calpain. Proc Natl Acad Sci U S A 84, 398–401.
Price, S. A., Held, B., and Pearson, H. A. (1998). Amyloid beta protein increases Ca2+ currents in rat cerebellar granule neurones. Neuroreport 9, 539–545.
Querfurth, H. W., Jiang, J., Geiger, J. D., and Selkoe, D. J. (1997). Caffeine stimulates amyloid beta-peptide release from beta-amyloid precursor protein-transfected HEK293 cells. J Neurochem 69, 1580–1591.
Querfurth, H. W., and Selkoe, D. J. (1994). Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33, 4550–4561.
Ramsden, M., Plant, L. D., Webster, N. J., Vaughan, P. F., Henderson, Z., and Pearson, H. A. (2001). Differential effects of unaggregated and aggregated amyloid beta protein (1–40) on K(+) channel currents in primary cultures of rat cerebellar granule and cortical neurones. J Neurochem 79, 699–712.
Ripova, D., Platilova, V., Strunecka, A., Jirak, R., and Hoschl, C. (2004). Alterations in calcium homeostasis as biological marker for mild Alzheimer’s disease? Physiol Res 53, 449–452.
Ripovi, D., Platilova, V., Strunecka, A., Jirak, R., and Hoschl, C. (2000). Cytosolic calcium alterations in platelets of patients with early stages of Alzheimer’s disease. Neurobiol Aging 21, 729–734.
Saito, K., Elce, J. S., Hamos, J. E., and Nixon, R. A. (1993). Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A 90, 2628–2632.
Scragg, J. L., Fearon, I. M., Boyle, J. P., Ball, S. G., Varadi, G., and Peers, C. (2005). Alzheimer’s amyloid peptides mediate hypoxic up-regulation of L-type Ca2+ channels. Faseb J 19, 150–152.
Shi, J., Townsend, M., and Constantine-Paton, M. (2000). Activity-dependent induction of tonic calcineurin activity mediates a rapid developmental downregulation of NMDA receptor currents. Neuron 28, 103–114.
Shi, X. P., Chen, E., Yin, K. C., Na, S., Garsky, V. M., Lai, M. T., Li, Y. M., Platchek, M., Register, R. B., Sardana, M. K., et al. (2001). The pro domain of beta-secretase does not confer strict zymogen-like properties but does assist proper folding of the protease domain. J Biol Chem 276, 10366–10373.
Sinha, S., and Lieberburg, I. (1999). Cellular mechanisms of beta-amyloid production and secretion. Proc Natl Acad Sci U S A 96, 11049–11053.
Smith, I. F., Green, K. N., and LaFerla, F. M. (2005). Calcium dysregulation in Alzheimer’s disease: recent advances gained from genetically modified animals. Cell Calcium 38, 427–437.
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., Nairn, A. C., Salter, M. W., Lombroso, P. J., Gouras, G. K., and Greengard, P. (2005). Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8, 1051–1058.
Takenouchi, T., and Munekata, E. (1994). Inhibitory effects of beta-amyloid peptides on nicotine-induced Ca2+ influx in PC12h cells in culture. Neurosci Lett 173, 147–150.
Taylor, S. C., Batten, T. F., and Peers, C. (1999). Hypoxic enhancement of quantal catecholamine secretion. Evidence for the involvement of amyloid beta-peptides. J Biol Chem 274, 31217–31222.
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., and Katzman, R. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30, 572–580.
Toescu, E. C., Verkhratsky, A., and Landfield, P. W. (2004). Ca2+ regulation and gene expression in normal brain aging. Trends Neurosci 27, 614–620.
Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S. F., Hao, Y. H., Serneels, L., De Strooper, B., Yu, G., and Bezprozvanny, I. (2006). Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell 126, 981–993.
Ueda, K., Shinohara, S., Yagami, T., Asakura, K., and Kawasaki, K. (1997). Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals. J Neurochem 68, 265–271.
Ulas, J., and Cotman, C. W. (1997). Decreased expression of N-methyl-D-aspartate receptor 1 messenger RNA in select regions of Alzheimer brain. Neuroscience 79, 973–982.
Veeranna, Kaji, T., Boland, B., Odrljin, T., Mohan, P., Basavarajappa, B. S., Peterhoff, C., Cataldo, A., Rudnicki, A., Amin, N., et al. (2004). Calpain mediates calcium-induced activation of the erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer’s disease. Am J Pathol 165, 795–805.
Walsh, D. M., Townsend, M., Podlisny, M. B., Shankar, G. M., Fadeeva, J. V., El Agnaf, O., Hartley, D. M., and Selkoe, D. J. (2005). Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation. J Neurosci 25, 2455–2462.
Wu, J., Kuo, Y. P., George, A. A., Xu, L., Hu, J., and Lukas, R. J. (2004). beta-Amyloid directly inhibits human alpha4beta2-nicotinic acetylcholine receptors heterologously expressed in human SH-EP1 cells. J Biol Chem 279, 37842–37851.
Yasar, S., Corrada, M., Brookmeyer, R., and Kawas, C. (2005). Calcium channel blockers and risk of AD: the Baltimore Longitudinal Study of Aging. Neurobiol Aging 26, 157–163.
Ye, C., Walsh, D. M., Selkoe, D. J., and Hartley, D. M. (2004). Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation. Neurosci Lett 366, 320–325.
Yoo, A. S., Cheng, I., Chung, S., Grenfell, T. Z., Lee, H., Pack-Chung, E., Handler, M., Shen, J., Xia, W., Tesco, G., et al. (2000). Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561–572.
Young, L. T., Kish, S. J., Li, P. P., and Warsh, J. J. (1988). Decreased brain [3H]inositol 1,4,5-trisphosphate binding in Alzheimer’s disease. Neurosci Lett 94, 198–202.
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GREEN, K., SMITH, I., LAFERLA, F. (2007). Role of Calcium in the Pathogenesis of Alzheimer’s Disease and Transgenic Models. In: Carafoli, E., Brini, M. (eds) Calcium Signalling and Disease. Subcellular Biochemistry, vol 45. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6191-2_19
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